The present invention relates to the fields of medicinal chemistry and ophthalmology. More specifically, this invention is directed to the provision of certain novel organic molecules which have an agonistic effect on beta-2 ("B.sub.2 ") adrenergic receptors. The physiological effect of the subject compounds is useful in the treatment of various conditions, particularly glaucoma. The invention is therefore also directed to the provision of methods of treatment which employ one or more of the subject compounds and corresponding pharmaceutical compositions.
Glaucoma is a progressive disease which leads to optic nerve damage, and, ultimately, partial or total loss of vision. The causes of this disease have been the subject of extensive studies for many years, but are still not fully understood. The principal symptom of the disease is an elevated pressure within the eye caused by excess intraocular fluid (i.e., "aqueous humor").
The reasons why the excess fluid accumulates are not fully understood. It is known that the elevated intraocular pressure ("IOP") can be at least partially controlled by administering drugs which affect either the production of aqueous humor within the eye or the flow of aqueous humor out of the eye. The glaucoma therapies currently available primarily involve the use of drugs which act to reduce production of aqueous humor by the ciliary body of the eye. These therapies have been generally effective in the majority of patients. However, it is not always possible to control chronic elevations of IOP by reducing the amount of aqueous humor production, particularly in cases where obstructed outflow of aqueous humor is contributing to the excess fluid level and consequent elevation of IOP. Moreover, the reduction of aqueous humor production creates a risk that the avascular tissues of the eye, particularly the lens and the cornea, will be damaged due to an inadequate supply of nutrients and/or hydration caused by the reduced production of aqueous humor. The possible use of agents which increase the outflow of aqueous humor to control IOP has therefore been a topic of great interest to scientists engaged in glaucoma research.
The compounds of the present invention share some common structural characteristics with epinephrine, which is a well-known compound having both B.sub.1 and B.sub.2 agonist activity. Epinephrine has been widely used as a vasoconstrictor, cardiac stimulant and bronchodilator for many years. The use of epinephrine and related sympathomimetic compounds (e.g. phenylephrine, norepinephrine and dipivaloyl epinephrine) in ophthalmology is also well known. These compounds have been used both alone and in combination with other types of drugs to control IOP in glaucoma patients. While the precise mechanisms of physiological action are not totally understood, it is believed that the compounds help to control IOP by both reducing the production of aqueous humor through an action on the ciliary body of the eye and increasing the outflow of aqueous through an action on the trabecular meshwork.
Although epinephrine and the related compounds mentioned above have been a very useful and important part of the ophthalmologist's drug arsenal for many years, there are practical limitations of the utility of these compounds. For example, the ability of the compounds to control chronic or extreme elevations of intraocular pressure is limited. Moreover, the compounds stimulate both B.sub.1 and B.sub.2 adrenergic receptors. As a result, the use of the compounds to control intraocular pressure may produce undesirable stimulation of receptors in other tissues within the body, such as the tissues of the cardiovascular system. This stimulation of the cardiovascular system may cause significant side effects, such as a marked increase in blood pressure, tachycardia and arrythmia. These side effects are particularly troublesome in elderly patients, who frequently are already afflicted with high blood pressure or other cardiovascular abnormalities.
In view of the foregoing, there is a need for an improved therapy which provides for more potent control of elevated IOP. There is also a need for a therapy which controls elevated IOP without causing significant side effects in other systems of the body, particularly the cardiovasculature system. A therapy which controls IOP by means of increasing the outflow of aqueous humor, without adversely affecting the normal production of aqueous humor, is also highly desirable.